What are the benefits for early diagnosis of cTTP?

3 min

Acute episodes
cTTP
Diagnosis/monitoring
Guidelines
Long-term outcomes
Treatment
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Make a diagnosis:

  • Among patients with severe thrombocytopenia and hemolytic anemia of unknown cause, the reduction in ADAMTS13 levels to < 10% of normal values confirms a diagnosis of TTP.1 The detection of autoantibodies (IgG) against ADAMTS13 further allows distinction between iTTP and cTTP.2 A diagnosis of cTTP is confirmed through genetic analysis and identification of causative ADAMTS13 mutations (homozygous or compound heterozygous).3
  • In most cases, cTTP diagnosis is not confirmed when patients experience their first episode of severe TTP because autoantibody detection via enzyme-linked immunosorbent assay (ELISA) sometimes fails to distinguish between iTTP and cTTP.3
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Adapt treatment for acute presentation:

  • Reduce mortality: TTP events have a mortality rate as high as 90% if untreated.4
  • Avoid unnecessary treatment as only a small proportion of patients with suspected TTP have the disease.5
  • The ultra-rarity of cTTP has prevented the full characterization of the clinical manifestations and optimal patient care. It is important to distinguish between iTTP and cTTP as ADAMTS13 supply through fresh frozen plasma (FFP) infusion is sufficient to resolve acute episodes in patients with cTTP, while patients with iTTP require intensive plasma exchange with FFP and immunosuppressors to survive.3
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Prevent further acute episodes for cTTP patients:

  • International Society on Thrombosis and Haemostasis (ISTH) TTP guidelines recommend treating cTTP with FFP (10–15 mL/kg) every 1–3 weeks to prevent further acute episodes, including severe thrombocytopenia and ischemic organ damage.6
  • British Society for Haematology Guideline recommends prophylaxis treatment: “ADAMTS13 prophylaxis should be considered for all patients with cTTP, with an individualised approach to dose and frequency according to symptoms, whether overt or non-overt.”7
  • According to diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) in Japan, “some patients require chronic treatment with periodic FFP transfusions, while others require episodic FFP transfusions only when their condition worsens. Determination of the FFP volume and transfusion duration should take into consideration platelet counts and occult blood scores.”8
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Manage long-term outcomes:

  • cTTP is a chronic disease leading to long-term outcomes including stroke and organ damage and affects patients’ quality of life (QoL) if untreated.9

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Abbreviations, Glossary and References

Abbreviations

ADAMTS13; A disintegrin and metalloproteinase with a thrombospondin motifs 13 

cTTP; Congenital TTP

ELISA; Enzyme-linked immunosorbent assay

FFP; Fresh frozen plasma

IgG; Immunoglobulin G

ISTH; International Society on Thrombosis and Haemostasis

iTTP; Immune-mediated TTP

QoL; Quality of life

TTP; Thrombotic thrombocytopenic purpura

 

Glossary

ADAMTS13; ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin motifs 13) is a constitutively active enzyme (plasma metalloprotease) that catalyzes the breakdown of ultra large and high molecular weight von Willebrand factor (VWF) into smaller multimers, reducing their thrombogenic potential, and maintaining hemostasis.9,10

Incidence; The rate of new cases or events over a specified period for the population at risk for a certain event.

Microangiopathic hemolytic anemia (MAHA); Process of red blood cell destruction within the microvasculature accompanied by thrombocytopenia due to platelet activation and consumption. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are primary forms of thrombotic microangiopathies.11

Prevalence; The proportion of a particular population found to be affected by a medical condition at a specific time.

Schistocyte; Circulating fragments of red blood cells commonly seen in blood smears from patients with thrombotic microangiopathies including TTP.12

Thrombocytopenia; Refers to a state of reduced peripheral platelets below normal levels (150x109/L) and can be caused by a wide variety of aetiologies that either decrease platelet production or increase platelet consumption.13

Thrombotic microangiopathy (TMA); TMA includes a diverse set of syndromes that can be hereditary or acquired, which can occur in children and adults with sudden or gradual onset.

TMA syndromes, despite being diverse, have a common set of clinical and pathological features: MAHA, thrombocytopenia, organ injury, vascular damage manifested by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall.14

Thrombotic thrombocytopenic purpura (TTP); TTP is a type of MAHA presenting with moderate or severe thrombocytopenia. There is associated organ dysfunction, including neurologic, cardiac, gastrointestinal and renal involvement; oliguria or anuric renal failure requiring renal replacement therapy is not typically a feature. TTP is confirmed by a severe deficiency (<10%) of ADAMTS13 activity.2

von Willebrand factor (VWF); VWF plays two key roles in hemostasis: 1) in primary (platelet-mediated) hemostasis, VWF binds to collagen and platelets thus promoting platelet activation and aggregation, and 2) in secondary (coagulation factor mediated) hemostasis VWF binds factor VIII (FVIII) protecting FVIII from rapid clearance. When VWF binds to collagen following vascular injury, it releases FVIII, leading to FVIII activation and initiation of the coagulation cascade.15,16

 

References

  1. Zheng, X.L., et al., ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost, 2020. 18(10): p. 2486-2495.
  2. Scully, M., et al., Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost, 2017. 15(2): p. 312-322.
  3. Sakai, K. and M. Matsumoto, Clinical Manifestations, Current and Future Therapy, and Long-Term Outcomes in Congenital Thrombotic Thrombocytopenic Purpura. J Clin Med, 2023. 12(10): p. 3365.
  4. Amorosi, E.L. and J.E. Ultmann, Thrombotic thrombocytopenic purpura: Report of 16 cases and review of the literature. Medicine, 1966. 45(2): p. 139-160.
  5. Novelli, C., et al., Clinical and Economic Impacts of a New Rapid ADAMTS-13 Assay for the Diagnosis of Suspected Thrombotic Thrombocytopenic Purpura. ISTH 2020 Congress, 2020.
  6. Zheng, X.L., et al., Good practice statements (GPS) for the clinical care of patients with thrombotic thrombocytopenic purpura. J Thromb Haemost, 2020. 18(10): p. 2503-2512.
  7. Scully, M., et al., A British Society for Haematology Guideline: Diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies. Br J Haematol, 2023. 203(4): p. 546-563.
  8. Matsumoto, M., et al., Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) in Japan 2023. Int J Hematol, 2023. 118(5): p. 529-546.
  9. Kremer Hovinga, J.A., et al., Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers, 2017. 3: p. 17020.
  10. Markham-Lee, Z., N.V. Morgan, and J. Emsley, Inherited ADAMTS13 mutations associated with Thrombotic Thrombocytopenic Purpura: a short review and update. Platelets, 2023. 34(1): p. 2138306.
  11. Arnold, D.M., C.J. Patriquin, and I. Nazy, Thrombotic microangiopathies: a general approach to diagnosis and management. CMAJ, 2017. 189(4): p. E153-E159.
  12. Zini, G., et al., ICSH recommendations for identification, diagnostic value, and quantitation of schistocytes. Int J Lab Hematol, 2012. 34(2): p. 107-116.
  13. Gauer, R.L. and M.M. Braun, Thrombocytopenia. Am Fam Physician, 2012. 85(6): p. 612-622.
  14. George, J.N. and C.M. Nester, Syndromes of thrombotic microangiopathy. N Engl J Med, 2014. 371(7): p. 654-666.
  15. Rauch, A., et al., On the versatility of von Willebrand factor. Mediterr J Hematol Infect Dis, 2013. 5(1): p. e2013046.
  16. Stockschlaeder, M., R. Schneppenheim, and U. Budde, Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis. Blood Coagul Fibrinolysis, 2014. 25(3): p. 206-216.
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